The chiral(S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo-[1,2-c]1,3,2-oxaz aborole (oxazaborole.sub.1) catalyzed borane reduction and reduction using (+) or (-) B-chlorodiisopinocampheylborane are two of the most effective methods for the enantioselective reduction of ketones to alcohols. With both methods the degree of enantiomeric purity obtained is dependent on the structure of the ketone.
The enantiomerically pure alcohol 1 is an important intermediate for the synthesis of (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-th iazin-6-sulfonamide 1, 1-dioxide and related compounds, which are useful in the treatment of ocular hypertension and glaucoma as disclosed in U.S. Pat. Nos. 5,240,923 and 5,153,192. ##STR1## wherein: R is H or Cl; and
R' is C.sub.1-6 alkyl, CH.sub.2 (CH.sub.2).sub.n OR", wherein R" is CH.sub.3 or (CH.sub.2).sub.n CH.sub.3 and n is 1-4, CH.sub.2 (CH.sub.2).sub.n X, wherein X is Br, Cl, or I, and n is 1-4, or (CH.sub.2).sub.n Ar, wherein Ar is unsubstituted phenyl, 3-methoxyphenyl, or 4-methoxyphenyl and n is 1 or 2.
Synthesis of 1 can be accomplished via an enantioselective reduction of 3 -(bromoacetyl)-2-thiophenesulfonamide 2 with (+)-B-chlorodiisopinocampheylborane [(+)-DIP-Chloride.TM.], followed by cyclization and N-alkylation with 3-bromo-1-methoxypropane. (See commonly assigned U.S. Pat. Nos. 5,240,923 and 5,153,192.) The method of the present invention has advantages over these procedures in that it is a catalytic reaction versus a reaction requiring a stoichiometric or excess amount of the reducing agent.
Commonly assigned U.S. Pat. No. 5,344,929 discloses the synthesis of 1 via a (+)-DIP-Chloride.TM. reduction of the bromo ketone 2 followed by cyclization to the cyclic chiral alcohol 8 and alkylation to 1. The method of the present invention (Scheme 1) involves the preparation of a racemic cyclic alcohol 4 followed by N-alkylation, oxidation to ketone 6, and re-reduction with oxazaborole.sub.1 reagent to give 1. The present process avoids the use of (+)-DIP-Chloride.TM..
The same sequence of reaction steps using borane tetrahydrofuran and catalytic amounts of oxazaborole.sub.1 gives less enantiomerically pure compound 1 even with different amounts of catalyst and at lower reaction temperature.
The present invention involves the synthesis of 1 with high enantioselectivity at about 30.degree. C. within a shortened reaction time and at a lower cost than prior methods. In addition, the precursor of the catalyst can be recovered by known procedures, see Jones, et al., J. Org. Chem. 56, 763-769 (1991) and Corey, J. Org. Chem. 53, 2861-2863 (1988).